Heterocycles reaction with amide anion

The presence of the propionamide fragment in the stmcture of the anti-inflammatory agent broperamole (125-1) is reminiscent of the heterocycle-based NSAID propionic acids. The activity of this agent may trace back to the acid that would result on hydrolysis of the amide. Tetrazoles are virtually always prepared by reaction of a nitrile with hydrazoic acid or, more commonly, sodium azide in the presence of acid in a reaction very analogous to a 1,3-dipolar cycloaddition. A more recent (and safer) version of the reaction noted later (see losartan, 77-4) uses tributyltin azide. In the case at hand, reaction of the anion of mefa-bromobenzonitrile (125-1) with sodium azide and an acid affords the tetrazole (125-2). Condensation of the anion from that intermediate with ethyl acrylate leads to the product from Michael addition saponiflcation gives the corresponding carboxylic acid (125-3). This is then converted to the acid chloride reaction with piperidine affords broperamole (125-4) [136]. 

The heterocycles react directly with alkali metals or undergo exchange reactions with, for example, sodium amide and hydride, n-butyllithium and thallium ethoxide, to form the TV-heteroaryl salts. The salts of the alkali metals exist as solvent separated ion-pairs or as contact ion-pairs (71JOC3091), as do the quaternary ammonium salts, whereas the salts of the heavier metals are generally considered to have a high N—metal covalent character. These characteristics, which can be modified by a change in the polarity of the solvent, control the reactions of the heteroaryl anions. 

Ketone dilithio-c /S-dianions (30, formed by treatment of /3 -stannylketones, RCOCH2-CH2SnBuCl2, with 4 equiv. of BuLi) react with imines and hydrazone selectively at the /3-anion portion to give dilithium enolate amides (31).82 Subsequent reaction with electrophiles gives y-amino ketones and related heterocycles. 

A major distinction for nucleophilic reactions with ambident anions is whether they proceed with kinetic or thermodynamic control.80 N-Substituted saccharins (10) should be thermodynamically more stable because of amide character than the isomeric pseudosaccharin (3) of imidate structure. In fact 3 may be rearranged thermally to 10 in an irreversible reaction.96 The threshold for thermodynamic control appears to be lowered for electrophiles with multiple bonds, e.g., formaldehyde, reactive derivatives of carboxylic acids, but also quaternary salts of N-heterocyclic compounds.80 It will be seen that in those cases substitution indeed occurs at the nitrogen, not necessarily through thermodynamic control. 

Ambident anions are mesomeric, nucleophilic anions which have at least two reactive centers with a substantial fraction of the negative charge distributed over these cen-ters ) ). Such ambident anions are capable of forming two types of products in nucleophilic substitution reactions with electrophilic reactants . Examples of this kind of anion are the enolates of 1,3-dicarbonyl compounds, phenolate, cyanide, thiocyanide, and nitrite ions, the anions of nitro compounds, oximes, amides, the anions of heterocyclic aromatic compounds e.g. pyrrole, hydroxypyridines, hydroxypyrimidines) and others cf. Fig. 5-17. 

So far the reactivity of epoxides has involved their use as an electrophile. However, oxtranyl anions can serve as functionalized nucleophiles in their own right. Thus, the sulfonyl substituted epoxide 107 can be deprotonated with -butyllithium to provide a stabilized anion which engages in facile Sn2 reaction with triflate 108 <03JOC9050>. Other examples of such stabilized epoxide anions include those derived from oxazolinyloxiranes (e.g., 110), which react with nitrones to provide the spirotricyclic heterocycles of type 112, Hydrolysis provides the epoxy amino acids 113, in which the carboxylic acid moiety was provided by the oxazoline nucleus and the amine functionality was derived from the nitrone <03OL2723>. A recent report has demonstrated that oxiranyl anions can also be stabilized by the amide functionality <03H(59)137>. 

The reaction of strongly basic amide anions, R -N-R, with chloro- or bromopyridines, -pyrimidines, and other heterocycles can lead to ring opening and subsequent ring closure to result in substituted amino-N-heterocycles (addition of nucleophile, ring opening, ring closure = ANRORC). 

Reaction of a suitably functionalized carbanion with an imine, and subsequent intramolecular trapping of the resultant secondary amide anion by an electrophile, is a useful procedure for the preparation of nitrogen heterocycles but in some cases the reaction fails because the imine is not sufficiently electrophilic. Jahangir... 

Similar to that of pyridine, the Chichibabin amination on quinoline and isoquinoline proceeds with alkali metal amides in liquid ammonia. In accordance to that, the reaction of quinoline with liquid ammonia initially forms a complex, which allows amide anion to add to the heterocyclic core of quinoline and isoquinoline bicycle, obtaining 2- or 4-aminoquinolines and 1-aminoisoquinolines, respectively, in good yields. ... 

Of the several syntheses available for the phenothiazine ring system, perhaps the simplest is the sulfuration reaction. This consists of treating the corresponding diphenylamine with a mixture of sulfur and iodine to afford directly the desired heterocycle. Since the proton on the nitrogen of the resultant molecule is but weakly acidic, strong bases are required to form the corresponding anion in order to carry out subsequent alkylation reactions. In practice such diverse bases as ethylmagnesium bromide, sodium amide, and sodium hydride have all been used. Alkylation with (chloroethyl)diethylamine affords diethazine (1), a compound that exhibits both antihista-minic and antiParkinsonian activity. Substitution of w-(2-chloroethyl)pyrrolidine in this sequence leads to pyrathiazine (2), an antihistamine of moderate potency. 

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